Our overall program is interested in fundamental issues regarding the evolution and chemotherapeutic potential of polyketide natural products. Using the power of organic synthesis, we seek to learn about the specific structural features found in polyketides, their effect on conformation, and the importance of conformation on biological activity. An underlying theme of this work is the development of practical methods applicable to the synthesis of stereochemically complex structural fragments found in polyketide natural products. During the research period, cationic cyclopropane methodology previously developed in our lab will provide access to ambruticin J, the putative biosynthetic intermediate to the antifungal agent ambruticin S. This material will be used to explore both chemical as well as biochemical conversion of ambruticin J to ambruticin S. The biochemical studies, performed in collaboration with Rolf Muller (University of Saarland) will provide fundamental information regarding the role of several post-PKS proteins including the epoxidase, AmbJ. In addition, intermediates necessary for ambruticin J synthesis will be converted to several labelled SNAC esters for feeding studies with the producing organism as well as isolated proteins. Analysis of the feeding studies will provide important information with regard to the unique biosynthesis of these cyclopropane containing polyketides. Section II of the Research Plan proposes new methodology, ether-transfer, applicable to the synthesis of acyclic polyketide fragments, pyran structural units and spiroketals. Like the cyclopropane methodology, ether-transfer is an efficient process that proceeds through a unique carbocationic intermediate and rapidly modifies simple starting materials into stereochemically complex synthetic fragments. Applications of the methodology include an efficient synthesis of the polyketides, diospongin A and B as well as neopeltolide. Biological and conformational studies on the neopeltolide polyketide core are proposed as a precursor to analogue design.